The subject-matter of the present invention is a process for releasing an active principle present in a multiple emulsion.
By definition, an emulsion consists of a dispersion of two mutually immiscible phases, such as generally a mixture of an aqueous phase and an oily phase. An emulsion is known as a direct emulsion when it comprises oil droplets dispersed in an aqueous phase, and as an inverse emulsion when it comprises water droplets dispersed in an oily phase.
Emulsions are conventionally obtained by shearing one of the phases within the other phase in the presence of at least one surfactant of the type: surface-active agents, polymers, and the like.
These surfactants are in fact chosen according to the nature of the emulsion envisaged. In the case of a direct emulsion, surfactants possessing a hydrophilic/lipophilic balance (HLB) of greater than 14 are favoured. On the other hand, surfactants with an HLB of less than 7 are preferably employed in inverse emulsions.
The term xe2x80x9cHLBxe2x80x9d (Hydrophilic Lipophilic Balance) denotes the ratio of the hydrophilicity of the polar groups of the surface-active molecules to the hydrophobicity of the lipophilic part of these same molecules; this is a term commonly used in the field of surfactants (see the treatise, xe2x80x9cTechniques de l""Ingxc3xa9nieurxe2x80x9d [xe2x80x9cTechniques of the Engineerxe2x80x9d], chapter A7610: xe2x80x9cLes agents de surfacexe2x80x9d [xe2x80x9cSurfactantsxe2x80x9d].
The emulsions incorporating these surfactants remain metastable for a sufficiently long period of time to allow them to be economically exploited in numerous fields of application, such as, for example, the cosmetic, coating, food and pharmaceutical industries.
In the specific case of multiple emulsions, at least two emulsions are superimposed. This relates, for example, to a dispersion, in an aqueous phase, of oily globules in which are dispersed tiny water droplets. Each of these two emulsions is, of course, stabilised by virtue of the incorporation, in its continuous phase, of a surfactant as defined above.
The present invention is targeted specifically at taking advantage of this type of water-in-oil-in-water multiple emulsion in order to transport at least one hydrophilic active principle and to allow its release in a controlled way.
Because of its three-phase structure, a water-in-oil-in-water multiple emulsion proves advantageously favourable to the encapsulation, in its internal water droplets, of hydrophilic active principles. The globules of the oily phase, in which globules the said water droplets are emulsified, confer an excellent protective barrier to the said principles with respect to the external environment. The transportation of these active principles via the multiple emulsion can thus be envisaged.
The object of the present invention is specifically to provide a process which makes it possible to control the release of this active principle encapsulated in a multiple emulsion.
Within the meaning of the present invention, xe2x80x9cmultiple emulsionxe2x80x9d is understood to define a water-in-oil-in-water emulsion comprising an inverse emulsion, Ei with an aqueous phase A1, in dispersion in the form of droplets of direct emulsion Ed, in a continuous aqueous phase A2, with the two emulsions Ed and Ei comprising, in their respective continuous phases, at least one surfactant in an amount sufficient to maintain them in stabilized and differentiated forms within the said multiple emulsion. The hydrophilic active principle present in the multiple emulsion under consideration according to the invention is present in the aqueous phase A1.
The step used to release this active principle from the multiple emulsion in fact takes advantage of the coalescence phenomena which can appear within the emulsion.
By definition, a coalescence is a breaking of a thin film established between two adjacent drops. In the case of a multiple emulsion, this type of coalescence can arise at two levels, the first between the internal water droplets present in an oily globule and the second between the interface of an oily globule and some of its internal water droplets.
Surprisingly, it proves to be possible to control these coalescence phenomena, that is to say to oppose them or, in contrast, to induce them, by virtue of the use in the said emulsion of specific concentrations of surfactants.
The studies carried out in the context of the present invention have thus made it possible to demonstrate that the coalescence phenomenon which more particularly determines an instability of the multiple emulsion favourable to the release of the active principle present in the internal water droplets A1 is that which takes place at the interface of an oily globule and of some of its internal water droplets A1. This results in a transfer of the active principle, initially present in these water droplets A1, to the aqueous phase A2. The active principle is then in contact with the external environment, originally comprising the said multiple emulsion, and can therefore exert its activity.
It advantageously proves possible to oppose or, in contrast, to induce the appearance of this coalescence phenomenon by intervening at the level of concentration of surfactant in the continuous aqueous phase A2 of the emulsion Ed. There exists a critical concentration threshold beyond which it is possible to trigger the escape of the contents of the internal water droplets A1 to the external environment.
Consequently, the present invention provides a process for releasing, in a controlled way, an active principle present in a multiple emulsion of water-in-oil-in-water type, characterized in that
the said emulsion comprises an inverse emulsion Ei with an aqueous phase A1 in which is incorporated at least one hydrophilic active principle, the said emulsion Ei being dispersed in the form of droplets of direct emulsion Ed in an aqueous phase A2 with the emulsions Ei and Ed stabilized by at least one surfactant present in their respective continuous phases, and in that
the said multiple emulsion is brought into the presence of a sufficient amount of an agent to convert it into a direct emulsion, so as to induce the release of the active principle present in the aqueous phase A1 of the emulsion Ei into the aqueous phase A2.
According to a favoured embodiment of the invention, the surfactant involved in the aqueous phase A2 of the emulsion Ed is present at a concentration below its critical concentration threshold.
Within the meaning of the invention, a critical concentration threshold is understood to define the value of surfactant concentration beyond which destabilization of the multiple emulsion is induced with the effect of releasing the active principle.
If the concentration of hydrophilic surface-active agent present in the aqueous phase A2 is below this concentration threshold, then no coalescence is observed for a period of the order of several months.
Conversely, if the concentration of hydrophilic surface-active agent present in the aqueous phase A2 is greater than or equal to this concentration threshold, then coalescence and therefore release take place over a time scale varying from a few days to a few minutes. The higher this concentration, the shorter the release time.
The release of the active principle will be regarded as complete when virtually all the droplets of the aqueous phase A1 have been released into the external aqueous phase A2. The release of the active principle will therefore be assessed as fast or slow according to the time taken to carry out the release of the droplets.
Advantageously, it thus proves to be possible to control the release of the active principle over a longer or shorter period of time by adjusting the difference in concentration between the critical concentration threshold and the final concentration obtained by addition of surfactant.
In fact, it has been observed that this concentration threshold could be expressed with respect to the critical micelle concentration, CMC, of the surfactant under consideration.
The critical micelle concentration is defined as the concentration beyond which the surface-active molecules combine together to form spherical clusters known as micelles (see, for example, xe2x80x9cGalenica 5, agents de surfaces et xc3xa9mulsionsxe2x80x9d [xe2x80x9cSurfactants and emulsionsxe2x80x9d], vol. 5.1, page 101, editor: Techniques et Documentation [Techniques and Documentation] (Lavoisier)).
However, the value of this concentration threshold, expressed with respect to the CMC, also varies according to the HLB value of the surfactant.
Thus, for a certain range of HLB values, the corresponding surfactants should be present in the aqueous phase A2 at a concentration below their critical micelle concentrations, if it is desired to avoid release of the active principle.
On the other hand, for another range of HLB values, the corresponding surfactants may be present up to a concentration far greater than their CMC, without this release of the active principle being observed.
As a general rule, for surfactants having an HLB of the order of 40, that is to say very hydrophilic, the concentration threshold is between 1 and 20 CMC.
In the case of surfactants having an HLB of between approximately 12 and 20, this concentration threshold is greater than 100 CMC.
Likewise, the diameter of the internal water droplets A1, the diameter of the droplets of emulsion Ed, the chemical nature of the active principle present in the aqueous phase A1 and the amount and type of surface-active agent present in the oily phase of the emulsion Ei affect the value of this critical concentration threshold.
All these parameters are therefore to be taken into consideration in assessing the critical concentration threshold for a specific surfactant present in the continuous aqueous phase A2 of the emulsion Ed.
This critical concentration threshold can be easily assessed, for a surfactant of given HLB, from preliminary tests according to the procedure described in Example 1 below.
This assessment can, for example, be carried out according to the procedure which consists in:
preparing a multiple emulsion which incorporates the active principle in its internal aqueous phase and which comprises a surfactant in the external aqueous phase A2 in an amount sufficient to stabilize the said emulsion,
adding, to the aqueous phase A2 of the said emulsion, increasing amounts of the said surfactant,
quantitatively determining, on conclusion of each addition of the said surfactant, the concentration of active principle which has or has not been released into the external aqueous phase, and
recording the concentration of surfactant beyond which a significant acceleration in the release kinetics is observed.
Generally, the concentration of surfactant is recorded beyond which 90% of the active principle initially present within the internal phase is found in the external aqueous phase in a time period of approximately 10 hours.
As regards the technique of quantitative determination used to estimate the concentration of the released active principle, it varies, of course, as a function of the nature of this active principle. It can be a conductimetric or potentiometric measurement, when the active principle is an ionic species, or alternatively a fluorescence spectroscopy technique, if the active principle is fluorescent.
Of course, a person skilled in the art is in a position to select the appropriate quantitative determination technique.
Advantageously, it therefore proves to be possible to induce the release of the active principle present in the claimed emulsion by bringing the direct emulsion Ed into contact with an agent, such that it causes, because of its presence and optionally its concentration, a transfer of the internal water droplets A1 to the aqueous phase A2, thus converting the multiple emulsion into a simple direct emulsion with release of the active principle into the external environment.